The long term objective of this research is to understand the genetic basis of blood pressure regulation, and consequently, its effects on hypertension in Mexican Americans. Identification of genes controlling blood pressure could allow assessment, at an early age, of an individual's risk for hypertension. This knowledge would enable intervention or implementation of preventive action. However, identification of such genes has been hampered by the multifactorial nature of blood pressure control. Mexican Americans have a higher prevalence of diabetes, higher adiposity, and poorer body fat distribution compared to non-Hispanic whites. Although these are all significant risk factors for hypertension, Mexican Americans have a similar or lower prevalence of hypertension than non-Hispanic whites. This paradoxical result may indicate that blood pressure control in Mexican Americans differs from non-Hispanic whites and/or blacks. Blood pressure regulation is a complex system, therefore we will focus on two of the biochemical pathways involved in the control of blood pressure, the renin-angiotensin system and kallikrein-kinin system. Specifically, a combination of statistical and molecular genetic methods will be used to identify and characterize genes that affect plasma or serum levels of angiotensinogen (AGT), tissue kallikrein, and angiotensin converting enzyme (ACE) in 40 families comprising approximately 1200 individuals living in a San Antonio barrio. For all individuals, the three intermediate phenotypes will be assayed, and genotypes will be obtained for seven known microsatellite DNA polymorphisms at or near the structural loci for AGT, ACE, renin, and tissue kallikrein. In addition, during this proposed project period, genotypes for 325 microsatellite DNA markers spaced 10 centiMorgans (cM) apart will become available on all members of these families. Complex univariate and multivariate segregation analysis will be used-to detect major genes that affect the intermediate phenotypes of blood pressure regulation. Lod-score linkage analysis will then be used to link each major gene to the polymorphisms of the associated structural loci. To locate other genes that may be linked to these intermediate phenotypes a variety of fast screening methods such as robust sibpair, relative pair, and robust variance components will be employed using the 10cM map. Results of these screening analyses will indicate which loci or chromosomal regions should then be used in the traditional lod-score linkage analysis. Any effects of the previously linked structural loci will be controlled for in this linkage analysis. After linkage using lod- score methods is found, we will genotype the family members for additional loci within the specific chromosomal region and perform multipoint linkage analyses to better localize the genes influencing the three intermediate phenotypes. Finally, all loci that have detectable effects on the intermediate phenotypes will be tested for their effects on blood pressure.